College of Pharmaceutical and Bioengineering, Shenyang University of Chemical Technology, Shenyang 110142, P. R. China.
State Key Laboratory of Medical Proteomics, National Chromatographic R. & A. Center, CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, P. R. China.
ACS Appl Mater Interfaces. 2024 Sep 11;16(36):47110-47123. doi: 10.1021/acsami.4c07494. Epub 2024 Aug 27.
Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to infection. Research indicates that circulating histones, as pathogenic factors, may represent a therapeutic target for sepsis. However, effectively clearing circulating histones poses a challenge due to their structural similarity to normal blood proteins, their low abundance in the bloodstream, and serious interference from other blood biomacromolecules. Here we design a dodecapeptide-based functional polymer that can selectively adsorb circulating histones from the blood. The peptide, named P1 (HNHHQLALVESY), was discovered through phage display screening and demonstrated a strong affinity for circulating histones while exhibiting negligible affinities for common proteins in the blood, such as human serum albumin (HSA), immunoglobulin G (IgG), and transferrin (TRF). Furthermore, the P1 peptide was incorporated into a functional polymer design, poly(PEGMA--P1), which was immobilized onto a silica gel surface through reversible addition-fragmentation chain transfer polymerization. The resulting material was characterized using solid nuclear magnetic resonance, thermogravimetric analysis, and X-ray photoelectron spectroscopy. This material demonstrated the ability to selectively and efficiently capture circulating histones from both model solutions and whole blood samples while also exhibiting satisfactory blood compatibility, good antifouling properties, and resistance to interference. Satisfactory binding affinity and efficient capture capacity toward histone were also observed for the other screened peptide P2 (QMSMDLFGSNFV)-grafted polymer, validating phage display as a reliable ligand screening strategy. These findings present an approach for the specific clearance of circulating histones and hold promise for future clinical applications in blood purification toward sepsis.
脓毒症是一种危及生命的器官功能障碍，由宿主对感染的失调反应引起。研究表明，作为致病因素的循环组蛋白可能代表脓毒症的治疗靶点。然而，由于其与正常血液蛋白结构相似、在血液中的丰度低以及严重干扰其他血液生物大分子，有效清除循环组蛋白具有挑战性。在这里，我们设计了一种基于十二肽的功能聚合物，可以从血液中选择性地吸附循环组蛋白。该肽，命名为 P1（HNHHQLALVESY），是通过噬菌体展示筛选发现的，对循环组蛋白具有很强的亲和力，而对血液中的常见蛋白质如人血清白蛋白（HSA）、免疫球蛋白 G（IgG）和转铁蛋白（TRF）几乎没有亲和力。此外，P1 肽被整合到功能聚合物设计中，聚（PEGMA-P1），通过可逆加成-断裂链转移聚合固定在硅胶表面上。使用固态核磁共振、热重分析和 X 射线光电子能谱对所得材料进行了表征。该材料表现出从模型溶液和全血样本中选择性和高效地捕获循环组蛋白的能力，同时还表现出令人满意的血液相容性、良好的抗污性能和抗干扰能力。筛选出的另一种肽 P2（QMSMDLFGSNFV）接枝聚合物也表现出对组蛋白的良好结合亲和力和高效捕获能力，验证了噬菌体展示作为一种可靠的配体筛选策略。这些发现为特异性清除循环组蛋白提供了一种方法，并为未来脓毒症血液净化的临床应用提供了希望。
